PROJECT SUMMARY Pre-term birth is linked to several morbidities and poor pulmonary, neurodevelopmental and systemic outcomes. Despite the documented association between inflammation and multi-organ damage in pre-term babies, there are currently no reports describing the interorgan innate immune crosstalk between the fetal liver, as a key regulator of inflammation, and other organs that can alter homeostasis. Furthermore, how the fetal hepatic innate immune response affects fetal metabolism during an inflammatory challenge is poorly understood. Our overarching aim is to determine the molecular mechanisms linking the fetal hepatic innate immune response and hepatocyte metabolism. Previously, our laboratory identified a developmentally-regulated, hepatic-specific pattern of expression for key inhibitory proteins of the transcription factor NF?B. As NF?B plays a central role in regulating innate immunity, these findings have led us to propose a new organizing hypothesis linking the fetal/neonatal hepatic innate immune response to not only pulmonary injury (as previously described in the parent RO1), but to hepatic and systemic metabolic disturbances. We hypothesize that the hepatic expression profile of the I?B family of NF?B inhibitory proteins leads to a sustained pro-inflammatory innate immune response to a systemic inflammatory challenge [intraamniotic lipopolysaccharide (IA LPS)] that contributes to severe hepatic inflammation, injury and alterations in metabolism. In this grant supplement, we propose two specific aims to test this hypothesis and determine the immunologic cross-talk between the fetal liver and hepatocyte function. In Aim 1, we will test whether the hepatic innate immune response is uniquely sustained and pro-inflammatory, and I?B?/NF?B signaling dependent after IA LPS challenge. In Aim 2, we will test whether this hepatic innate immune response contributes to paracrine effects on hepatocyte function leading to systemic metabolic consequences. Our hypothesis represents a paradigm shift in how we approach the prevention of fetal multi-organ damage by linking a sustained pro-inflammatory innate immune response mediated by hepatic I?B?/NF?B signaling to metabolic disturbances and subsequent abnormal development. These studies will provide the foundation for translational work aimed at pharmacologically targeting I?B? /NF?B signaling to prevent local (hepatic) and systemic damage in the metabolic compromised neonate.